Study Summary – The authors followed up children under 5 years of age, who presented with AGE in a large pediatrics practice in New Orleans, between 2004 and 2009. Primary care physician office visits, emergency department visits, and hospital admissions were identified by review of records. RV testing was performed only on those who were seen at the hospital. Overall, about 16,000 children were included in this study.

Results – For 2006–2007, 2007–2008, and 2008–2009, 11.1%, 40.3%, and 45.6% of age-eligible children, respectively, received 1 dose of RV5. As compared with 2004–2005 (before RV5), in 2007–2009, there was a significant decrease in all-cause AGE office visits (23%) and hospitalizations (50%). RV-positive cases (emergency department visits or hospitalizations) decreased by 67%. The decrease in RV-positive cases was more evident among children who were younger than 2 years (81%), with a strong trend among those who were aged 2 to <5 years (41%).

Conclusion – This study adds more evidence that the introduction of the pentavalent rotavirus vaccine led to a significant decrease in all-cause AGE hospitalizations, and especially rotavirus-caused AGE. Taken together with the previous 3 studies we’ve reviewed, the evidence seems very solid and is strongly suggestive of a correlation between the introduction of RV5 in 2006, and significant decreases in AGE hospitalizations. The authors of the above study concluded as such:

Increased use of RV5 in a pediatric practice was associatedwith fewer AGE office visits and hospitalizations. The reductionwas specific for RV-positive AGE and seen among children whowere targeted for immunization as well as older groups, suggestinga herd-immunity effect.

Two new studies, published online in The Lancet (the full text can be accessed here and here; free registration to The Lancet required), have produced similar results to the results of a similar US study on which I reported here at Vaccine Central which showed the RotaTeq pentavalent rotavirus vaccine to be 45% in reducing all cause gastroenteritis hospitalization rates, an excellent track record given that the rotavirus is credited with causing up to 50% of all cause gastroenteritis hospitalizations in children. At that time, I concluded that although the study showed a strong correlation between the introduction of the vaccine and the reduction in AGE hospitalization rates, given that we only had 2 data points, we couldn’t make a direct causation link between the two events, and that further evidence was needed in order to reach that conclusion.

That further evidence has been provided by the above-mentioned 2 studies. I will summarize each study separately.

Study Summary-This was a multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh (2 year observation period), and urban and periurban Nha Trang, Vietnam (One and a half years observation period). Infants aged 4–12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants who received vaccine or placebo were visited once a month to remind parents to bring their child to a clinic or hospital if their child developed symptoms of gastroenteritis. Any adverse reactions occurring within 14 days of receipt of each dose (both vaccine and placebo) were recorded.

To assess immune responses to vaccination, a small amount of venous blood was obtained immediately before the first dose of study vaccine or placebo was given and about 14 days after the third dose was given in a subset of around 300 participants (around 150 per site).

The primary outcome was severe rotavirus gastroenteritis, irrespective of serotype, occurring 14 days or more after the third dose of vaccine or placebo until end of study. Secondary outcomes were efficacy of vaccination against rotavirus gastroenteritis of any severity, proportion of participants with a serious adverse event within 14 days of any dose, and the proportion of participants with seroresponse for antirotavirus IgA.

Results – Overall, the vaccine had a success rate of 48.3% in preventing severe rotavirus gastroenteritis (RVGE), 42.5 % reduction in any severity RVGE, and 27% in severe GE of any cause. Seroresponse, rotavirus antibodies present in the blood stream, was significantly higher in the vaccinated groups (87.8%) than the placebo group (18.2%). Serious side effects within 14 days of any dose were virtually the same for both the vaccine and the placebo group (Table 5).

Conclusion – The study is methodologically sound. It is randomized, double-blind and placebo-controlled. The results strongly suggest that the pentavalent rotavirus vaccine reduces both RVGE and all cause GE rates, by about 48% and 27% respectively, while being safe and inducing a strong immune system response in the participants. Side effects for the vaccinated children were comparable to those of the children in the control group.

Conflicts of Interest – The study was designed and run by Merck, one of the vaccine makers, with input from World Health Organization staff and site investigators. Here is the complete “Role of funding source” section from the study:

The study was designed by Merck investigators, with substantial input from PATH staff and site investigators. Merck had direct oversight or participation in every stage of the study. Merck also participated in pharmacovigilance, organised and led the data and safety monitoring board meetings, and did the data analysis. Staff from PATH independently monitored study execution at sites and participated in pharmacovigilence, data analysis, and data and safety monitoring board meetings. All authors had full access to the data, and the corresponding author had final responsibility for the decision to submit for publication.

Study Summary – The design of this study is identical to that of the Asian study. The only difference is the number of children; the African study enrolled about twice as many subjects. 5468 infants, in Ghana, Kenya and Mali, were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735) with an observation period of 23 months. Immune responses to vaccination were assessed in a subset of around 450 participants (around 150 per site). Primary and secondary outcomes were identical to the Asian study.

Results – Overall, the vaccine had a success rate of 39.3% in preventing severe rotavirus gastroenteritis (RVGE), 30.5 % reduction in any severity RVGE, and 10.6% in severe GE of any cause. Seroresponse, rotavirus antibodies present in the blood stream, was significantly higher in the vaccinated groups (78.3%) than the placebo group (20.1%). Serious side effects within 14 days of any dose were virtually the same for both the vaccine and the placebo group (Table 5).

Conclusion – The study is methodologically sound. It is randomized, double-blind and placebo-controlled. The results strongly suggest that the pentavalent rotavirus vaccine reduces both RVGE and all cause GE rates, by about 30.5% and 10.6% respectively, while being safe and inducing a strong immune system response in the participants. Side effects for the vaccinated children were comparable to those of the children in the control group.

Conflicts of Interest – The study was designed and run by Merck, one of the vaccine makers, with input from World Health Organization staff and site investigators. Here is the complete “Role of funding source” section from the study:

The study was designed by scientists from Merck, with substantial input from PATH staff and site investigators. Merck had direct oversight or participation in every stage
of the study. Merck also participated in pharmacovigilance, organised and led the data and safety monitoring board meetings, and did the data analysis. Staff from PATH
independently monitored study execution at sites and participated in pharmaco vigilance, data analysis, and data and safety monitoring board meetings. All authors had full access to the data, and the corresponding author had final responsibility for the decision to submit for publication.

Where do these 3 studies leave us?

It is important to note, that while all 3 studies (US, Asia and Africa) point to the same direction, and all three show that the pentavalent rotavirus vaccine does have a substantial effect in reducing all cause gastroenteritis cases, the actual effect size of the vaccine seems to vary considerably from region to region. The US study reported a 45% decrease in all cause AGE hospitalization rates; the Asian study reported a 27% decrease while the African study reported a 10.6% decrease. The authors have picked up on this as well and have included this issue in their discussion. For example, this is what they say in the African study:

Although the efficacy noted in this trial and the accompanying study in Asia were significant, both estimates of efficacy were lower than that reported with pentavalent rotavirus vaccine in developed countries or in developing countries in Latin America. Direct comparisons of results from previous studies of pentavalent rotavirus vaccine are limited by differences in study design, collection procedures, and clinical scoring systems. However, the comparatively low efficacy noted in this study is consistent with the low efficacy with another rotavirus vaccine reported in Africa compared with more developed countries, and with the low efficacy reported in low-income populations with other orally administered vaccines. The immunogenicity of pentavalent rotavirus vaccine in our study population was substantially lower than were results obtained in more developed countries.

So why this variation? It’s hard to say, it does not seem clear to me from these studies at least, why there would be such variation. As far as the US study is concerned, part of the answer may have to do with the fact that it was a retrospective study, comparing rates before vaccination with rates after vaccination, thus lacking a proper control group which the Asian and African studies had. On the other hand geography seems to have an important effect, as even within the Asian group there were some considerable differences between the two countries.

Nevertheless, while these issues may need more time to be sorted out, the take-home message is a very encouraging one: the pentavalent rotavirus vaccine seems to have a considerable positive effect in reducing all cause gastroenteritis rates in infants, while being safe. And given that there are an estimated 527,000 rotavirus deaths worldwide per year, even if the true effect turns out to be the lowest value of the three, the 10.6%, we are still talking about roughly 56,000 lives saved per year, with basically next to zero side effects from the vaccine.

A new analysis, published online by The Journal of Infectious Diseases, takes a look at acute gastroenteritis hospitalization (AGE) rates among US children under 5 years old, before and after the introduction of the first Rotavirus vaccine, RotaTeq (RV5) in early 2006. The objective of this analysis was to see if there was any change in gastroenteritis hospitalization rates after the vaccine was licensed for use among infants in the United States. The study I am referring to is this one:

Study Summary -The authors gathered approximately 100% complete AGE hospitalization rates for children under 5 years of age, from 18 states, accounting for 49% of the U.S. under 5 children population. MedianAGE hospitalization rates from the pre-vaccine years of 2000-2006 were compared with median AGE hospitalization rates from 2007, the first year after the vaccine, and 2008.

Results – Overall AGE hospitalization rates went down by 16% in 2007 and decreased by 45% in 2008. By age group, the reductions line up like this:

0-2 months – 28%

3-5 months – 42%

6-23 months – 50%

24-59 months – 45%

Prior to RV5 introduction, children in the 6-11 month age group had the highest hospitalization rates; after vaccine introduction children in the 0-2 month age group had the highest hospitalization rates, and showed the lowest decreases. Given that the first dose of the vaccine is given at 2 months of age, this result is to be expected.

All states experienced reduced rates of hospitalization with the exception of two: Arizona and Nevada which experienced increases of 17.1% and 12.9% respectively, prompting the study authors to note that :

It is noteworthy that 2 participating states, Arizona and Nevada, had 2008 rotavirus seasons that were similar to those in prior seasons. As data become available, it will be of interest to evaluate whether these 2 states had different patterns of RV5 coverage that could explain their distinct 2008 rotavirus seasons.

How should we interpret this analysis? Well, as alwasy the rule of thumb is that one study never proves anything. However, this study does provide strong evidence for a correlation between the RV5 vaccine and lower AGE hospitalization rates. We have to be careful though to remember that correlation does not necessarily imply causation. Given that the post-vaccine data is only for two years, the conclusion that the introduction of the rotavirus vaccine lowered AGE hospitalization rates seems unwarranted at this point. It will be interesting to see if these results hold up 2, 5, 10 years down the road.

Nevertheless, the fact that rotavirus is responsible for 50% of AGE hospitalizations, and the fact that the reductions were more pronounced in the age groups that received vaccines, as compared to the 0-2 month olds who do not, suggests a correlation to some degree. Furthermore, while there is year-to-year variability in AGE hospitalization rates, the 2008 reduction “well exceeded the range of this variability” further suggesting an effect other than regular variability. Lastly, the “consistency of the decrease in acute gastroenteritis hospitalization rates across most states and specifically during the rotavirus season strongly support that these changes resulted from the RV5 vaccination, but the lack of timely national data on RV5 coverage precluded correlation of the decreases with vaccine uptake.” (emphasis added)

Conclusion – This analysis provides good evidence for an association between the introduction of the RV5 vaccine and a considerable reduction in AGE hospitalization rates, especially for 2008. It also provides strong evidence that there may be a correlation between the two, however the lack of nationals RV5 coverage data, and the fact that the post vaccine years provide only 2 data points, preclude us from concluding that the decreases are due to the vaccine. Only further confirmatory studies down the road can provide that additional support that would be needed to conclusively say that the rotavirus vaccine has had a direct effect in reducing AGE hospitalization rates. Until then, we must stick with the strong suggestion that it does.